Epithelial ovarian carcinoma results in the highest mortality of all gynecologic cancers in the United States. As for most cancers, this tumor arises from a multistep, multigenic process involving inherited and/or somatically acquired mutations. Segregation and linkage analyses suggest that 5-10% of all ovarian cancers are associated with the inheritance of a mutant gene conferring autosomal dominant susceptibility, and the BRCA1 gene on chromosome 17q is believed to account for most of these hereditary cases. Germline mutations in BRCA 1 are associated with an enigmatic cancer susceptibility profile. Affected families may suffer from ovarian cancer, breast cancer, or both; furthermore, some women with a mutant BRCA 1 allele remain cancer free while relatives acquire early-onset malignancies. Currently available data indicate that specific mutations are not associated with degree of penetrance or with susceptibility to one or the other tumor type, and preliminary data indicate that BRCA 1 associated ovarian carcinomas display a distinct profile of histopathologic and clinical features. The long-term objective of this project is to determine the genetic mechanisms(s) of BRCA 1 associated ovarian tumorigenesis, especially in regard to penetrance, ovarian specificity, and the nature of somatic molecular genetic alterations in these cancers. Specific aims are to address the hypotheses that the co-inheritance of mutant alleles from other cancer-related genes may modify ovarian cancer predisposition from BRCA 1 and that the ovarian tumors from women with germline BRCA 1 mutations display a common spectrum of somatic molecular genetic alterations, which would serve to distinguish this subclass of ovarian cancers from the larger class of "sporadic" tumors. The first goal will be accomplished by collecting normal tissue DNA samples from ovarian cancer patients with documented mutations in the BRCA 1 gene, and analyzing these samples for the presence of germline variation in three genetic loci previously associated with increased cancer susceptibility: P53, ATM and HaRAS. Preliminary data indicate that a subtle, inherited alteration in the P53 gene is found in a high percentage of ovarian cancer patients with germline mutations of BRCA 1. The second goal will be accomplished by analyzing ovarian cancer tissues from the same patient population for somatic alterations in genes associated with ovarian carcinogenesis, including the erbB-2 and ras oncogenes, the P53 tumor suppressor gene, and microsatellite instability, and them comparing these data with those obtained from sporadic tumors matched for clinicopathologic variables. Successful completion of the proposed studies is expected to facilitate risk assessment for hereditary ovarian cancer, and to provide significant insight into the molecular genetic mechanisms of hereditary ovarian tumorigenesis.